There is an unmet medical need for the therapy of leukemia and lymphoma of B cell origin as most adult patients remain incurable. The most potent antitumor effect mediated by the immune system occurs in the setting of allogeneic stem cell transplantation (HSCT). However, most patients are not eligible for this therapy. The objective of this project is to engineer autologous lymphocytes to endow them with the features that would render them equally powerful as allogeneic lymphocytes, and therefore avoid the toxicity and make the therapy routinely available to patients who relapse after initial therapy. Based on recent pilot results in patients with chronic lymphocytic leukemia (CLL), our long term goal is to develop a novel therapy using cell transfer therapy of engineered T cells expressing chimeric antigen receptors (CARs) that bind CD19 for the treatment of B cell malignancies. The key questions currently facing the field are how to: (1) enhance the potency and specificity of autologous T cells so that HSCT can be avoided, and (2) develop mechanisms to increase the persistence of CAR T cells so that they are resistant to the immunosuppressive tumor microenvironment. CARs are an attractive approach to address these issues, because they are off the shelf and HLAindependent. However, in order to establish clinical proof of concept that will be required to justify randomized clinical trials, it will be necessary to optimize vector design, as seemingly small changes in CAR design can have major effects on the antitumor potency of the engineered T cells. Prior preclinical and clinical studies have shown safety of the CAR approach, but efficacy has been disappointing, in part due to poor in vivo survival of CAR expressing cells. Since these early studies utilized CARs containing only a 1st generation single CD3&#950; signaling chain, our hypothesis, based on strong pre-clinical data and early phase I clinical results is that our 2nd generation CARs that harbor additional costimulatory domains will augment survival and/or function of CAR-expressing cells in lymphodepleted patients. Our specific aims are to conduct a phase IIa study to: (1) Test the safety, feasibility and tolerability of 3rd generation anti-CD19 CARs in patients with advanced chronic lymphocytic leukemia; 2) Determine the persistence and function of the CAR T cells in patients by measuring the engraftment and trafficking of CAR T cells to the tumor microenvironment, and the duration of B cell aplasia as a proof of mechanism. Other studies will determine safety of the lentiviral vector. Together, these studies will test the central hypothesis that costimulatory signaling domains will provide a selective survival advantage to CAR T cells in patient with CLL, providing proof of mechanism for this new approach. Our approach addresses a clear unmet medical need, as the only curative approach for most patients with relapsed leukemia is HSCT; our CARs could conceivably replace the allogeneic HSCT with an autologous CAR approach, and thereby decrease toxicity and expense associated with transplantation. Finally, the scientific principles evaluated are broadly applicable to other cancer therapies.